Abstract
Idiopathic pulmonary fibrosis (IPF) is a complex disease involving various cell types. Macrophages are essential in maintenance of physiological homeostasis, wound repair and fibrosis in the lung. Macrophages play a crucial role in repair and remodeling by altering their phenotype and secretory pattern in response to injury. The secretome of induced pluripotent stem cells (iPSC-cm) attenuates injury and fibrosis in bleomycin injured rat lungs. In the current study, we evaluate the effect of iPSC-cm on gene expression and phenotype of interstitial macrophage in bleomycin injured rat lungs in vivo. iPSC-cm was intratracheally instilled 7 days after bleomycin induced lung injury and assessed 7 days later and single cell isolation was performed. Macrophages were FACS sorted and microarray analysis was performed. We characterized changes in the rat lung interstitial macrophages using transcriptional profiling. iPSC-cm reduced the total collagen content of the lung and reduced different macrophage populations. Gene set enrichment analysis revealed involvement of three essential pathways (a) immune modulation, (b) branching morphogenesis and (c) canonical Wnt signaling. This study demonstrates that iPSC-cm reduces fibrosis in bleomycin injured rat lung by partially altering the macrophages and regulating their gene expression.
Highlights
Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonias and is characterized by progressive loss of alveolar epithelial integrity due Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.10 Pathology of the University Hospital of Lübeck and the Leibniz Research Center Borstel, Borstel, Germany11 Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Groβhansdorf, GermanyStem Cell Reviews and Reports (2018) 14:412–424IPF is not known, recent evidence suggest a very complex and dynamic process involving various cell types including macrophages [7].Macrophages play a very critical role in defense, metabolism and maintenance of homeostasis
Immunostaining revealed increased macrophage staining in bleomycin injured lungs treated with control media CD68 (Fig. 1b), CD206 (Fig. 1e), and CD86 (Fig. 1h)
Macrophages showed reduced staining for CD68 (Fig. 1c), CD206 (Fig. 1f), and CD86 (Fig. 1i) 7 days after treatment with induced pluripotent stem cells (iPSC)-cm, compared to animals treated with control media (Fig. 1b and e)
Summary
Macrophages demonstrate distinguished plasticity in acquiring phenotypes that can either promote or resolve fibroproliferative response to injury. Based on their location, pulmonary macrophages are divided into alveolar macrophages (AMs) residing in airways and interstitial macrophages (IMs) located in lung parenchymal tissue [8]. Recent advances have changed our understanding of macrophage phenotypes, plasticity and their specific role in fibrosis [9]. Based on some murine studies, it is considered that they assume a pro fibrotic phenotype [12]. Targeting these cells to resolve fibrosis could be a promising novel approach
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